Clinical Phenotypes of Patients with Obstructive Sleep Apnea-Hypopnea Syndrome: A Cluster Analysis

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Clinical Phenotypes of Patients with Obstructive Sleep Apnea-Hypopnea Syndrome: A Cluster Analysis

Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a prevalent sleep-disordered breathing condition associated with systemic complications, including cardiovascular, metabolic, and neurocognitive sequelae. Despite its widespread recognition as a heterogeneous syndrome, the identification of distinct clinical phenotypes remains limited, particularly in Chinese populations. This study represents the first large-scale cluster analysis of OSAHS patients in Southern Jiangsu, China, aiming to elucidate clinically meaningful subgroups based on demographic, symptomatic, and cognitive characteristics.

Study Design and Population

The retrospective analysis included 1,044 consecutive OSAHS patients diagnosed at the Sleep Center of the Second Affiliated Hospital of Soochow University between January 2014 and December 2018. Inclusion criteria required an apnea-hypopnea index (AHI) >5 events/hour, completion of the Epworth Sleepiness Scale (ESS) and Montreal Cognitive Assessment (MoCA), and absence of major central nervous system disorders or therapies affecting sleep architecture. The cohort comprised predominantly male patients (97.4%), with ages ranging from 14 to 83 years (mean 42.3 ± 11.7 years).

Variables and Assessments

Fourteen variables were analyzed, categorized into:

  1. Demographics: Sex, age, body mass index (BMI), smoking, and alcohol use
  2. Symptoms:
    • Nocturnal: Snoring, breathing pauses, apnea-related awakenings, nocturia, leg movements, dreams, nightmares, sleepwalking
    • Daytime: Morning fatigue, headache, thirst
    • Insomnia-related: Difficulty falling asleep, early awakenings
  3. Comorbidities: Diabetes, hypertension, cardiovascular diseases, respiratory disorders, thyroid dysfunction, and transient ischemic attacks
  4. Scales: ESS (daytime sleepiness) and MoCA (cognitive function)

Polysomnography (Alice 6 or Compumedics E Series) recorded AHI, oxygen desaturation index (ODI), time spent below 90% oxygen saturation (TS90%), arousal indices, and sleep stage percentages. All recordings exceeding 4 hours underwent expert validation.

Statistical Approach

A two-step clustering algorithm (IBM SPSS v22) categorized patients into subgroups, followed by:

  • ANOVA/Kruskal-Wallis tests for continuous variables (normal/non-normal distributions)
  • Chi-square/Fisher’s exact tests for categorical variables
  • Significance threshold: P < 0.05

Identified Clinical Phenotypes

Cluster analysis revealed four distinct subgroups with unique clinical and polysomnographic profiles:

1. Classic Phenotype (30.5%, n=318)

  • Demographics: Exclusively male, mean age 41.9 ± 10.7 years, BMI 27.6 ± 3.2 kg/m²
  • Symptoms: Universal snoring (100%) and breathing pauses (100%), frequent apnea-related awakenings (42.5%), highest ESS score (median 10 [IQR 6–14])
  • Comorbidities: Intermediate burden (median 1 [0–1])
  • Polysomnography: Severe OSAHS (median AHI 45.8 [24.5–65.9]), marked hypoxia (TS90% 13.7% [3.8–37.3]), prolonged apneas (longest apnea 65.0s [52.6–81.0])

2. Minimally Symptomatic Phenotype (22.1%, n=231)

  • Demographics: Male-only, younger (41.1 ± 12.9 years), BMI 27.6 ± 4.8 kg/m²
  • Symptoms: Lowest ESS (median 8 [5–12]), absent breathing pauses (100%), rare apnea-related awakenings (10.4%)
  • Comorbidities: Minimal (median 0 [0–1])
  • Polysomnography: Moderate severity (AHI 30.3 [13.1–55.3]), mild hypoxia (TS90% 5.4% [0.9–19.7]), shorter apneas (56.0s [43.0–74.0])

3. Cognitive Impairment Phenotype (11.8%, n=123)

  • Demographics: Predominantly female (88.6%), older (50.1 ± 14.2 years), lower BMI (26.4 ± 3.7 kg/m²)
  • Symptoms: Highest nocturnal/insomnia symptoms, lowest MoCA (median 26 [22–28]), intermediate ESS (9 [4–14])
  • Comorbidities: Highest burden (median 1 [0–1])
  • Polysomnography: Mildest OSAHS (AHI 23.2 [10.7–47.6]), least hypoxia (TS90% 3.6% [0.8–15.1]), preserved slow-wave sleep (16.1% [9.7–20.4])

4. Daytime Symptom Phenotype (35.6%, n=372)

  • Demographics: Male-only, age 41.6 ± 11.1 years, BMI 27.6 ± 3.7 kg/m²
  • Symptoms: Maximum morning fatigue/headache/thirst (100%), intermediate ESS (9 [5–14]), highest MoCA (27 [26–28])
  • Comorbidities: Low (median 0 [0–1])
  • Polysomnography: Severe OSAHS (AHI 44.6 [23.4–66.2]), comparable to Cluster 1 in hypoxia (TS90% 15.9% [3.8–35.7]) but shorter apneas (65.3s [50.0–80.4])

Polysomnographic Comparisons

Significant inter-cluster differences emerged in:

  • AHI (H=54.200, P<0.001): Highest in Clusters 1/4, lowest in Cluster 3
  • Hypoxia markers:
    • ODI (H=50.736, P<0.001)
    • TS90% (H=65.938, P<0.001)
    • Lowest SpO₂ (H=47.849, P<0.001)
  • Sleep architecture:
    • Respiratory effort-related arousal (H=56.641, P<0.001)
    • Slow-wave sleep percentage (H=42.362, P<0.001)

Notably, Clusters 1 and 4 showed equivalent OSAHS severity by AHI but diverged in cognitive status (P=0.004), smoking (P<0.001), and alcohol use (P<0.001).

Clinical Implications

  1. Cognitive Impairment Subgroup:

    • First identification in OSAHS populations, predominantly peri-menopausal women with preserved sleep metrics (lower AHI, higher slow-wave sleep)
    • Supports estrogen’s role in neuroprotection and vascular health, aligning with evidence of white matter injury in female OSAHS patients

  2. Symptom-Severity Discordance:

    • Minimally symptomatic patients (Cluster 2) demonstrated significant respiratory dysfunction despite low symptom burden, highlighting limitations of symptom-guided diagnosis
    • Daytime Symptom group (Cluster 4) exhibited prompt healthcare-seeking behavior due to distressing morning symptoms, suggesting targeted public health messaging

  3. AHI Limitations:

    • Poor correlation between AHI and cognitive/functional outcomes (e.g., Cluster 3’s low AHI vs. marked cognitive decline)
    • Supports multidimensional assessment integrating MoCA, symptom patterns, and comorbidities

  4. Sex-Specific Pathophysiology:

    • Female-predominant cognitive impairment group underscores hormonal and vascular interactions requiring sex-stratified management

Methodological Considerations

  • Strengths: Large sample size, inclusion of neurocognitive metrics, comprehensive polysomnography
  • Limitations: Retrospective design, single-center recruitment, potential selection bias in female representation
  • Future Directions: Prospective validation, hormonal/neuroimaging correlates, longitudinal outcomes

This phenotypic stratification enables personalized therapeutic strategies, emphasizing cognitive screening in OSAHS management, particularly for female and aging populations.

doi.org/10.1097/CM9.0000000000001649

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